Integrase deficient lentiviruses (IDLV) are non-replicative lentiviruses containing mutations in the catalytic domain of the viral integrase. As a consequence, circular cDNA off-products of the retrotranscription named 1-LTR and 2-LTR accumulate in the cell nucleus but are not able to integrate into the host genome (FIG. 1) (Yáñez-Muñoz R J et al., Nat. Med. 2006, 12: 348-353). As any other exogenous DNA those intermediates can integrate in the cellular DNA at equal frequencies (among 103 to 105/cell).
The extrachromosomal (episomal) properties of the IDLV-derived cDNAs has been avoids some of the disadvantages of classical lentiviruses. Episomal vectors display minimal interference with the cellular genome, thus minimizing both the position dependent expression profile of the transgenes delivered by the virus and the potential damage due to insertional mutagenesis. Despite the early enthusiasm captured for these novel vectors, a major concern is derived from their inability to replicate autonomously. Then the successive cell divisions lead the extinction of the lentivector sequences by the dilution of cells bearing the episomes, limiting their applicability to a narrow set of tissues and cells with low to null mitotic activity, as the nervous system. It follows that gene therapies based on these vectors are restricted to target senescent tissues or cells with very low rate of cell divisions to ensure permanence of the corrected phenotype driven by the transgene. Unfortunately many potentially treatable diseases by gene therapy rely on modify highly dividing cells or tissues undergoing life-spanning cell divisions like hematopoietic or epithelial stem cells as well as stem/iPS cells-based cures that are not target of these vectors.